While considerable progress has been achieved in understanding basic mechanisms of glomerular and renal fibrosis, the absence of a true experimental model for human FSGS has made it difficult to clearly understand how these basic mechanisms apply to human idiopathic FSGS. A second major limitation has been that mesenchymal cells such as mesangial cells and interstitial cells and tubular epithelial cells have received the most attention in defining pathways of sclerosis and fibrosis, while a less well studied cell, the podocyte, plays a major role in the injuries leading to FSGS. Recently, the NIDDK initiated a prospective, controlled, randomized trial to study the treatment of FSGS in children and young adults. Our studies aim to perform state-of-the art analysis of the renal biopsy tissue obtained for patient entry into this multicenter study, along with additional cases from our archival files, with a total of >2000 cases, with >200 in children. We will analyze histologic patterns of injury and correlate them with expression by specific glomerular cell types of protein and mRNA of mediators of cell differentiation, proliferation, ECM modulation and inflammatory modulators. These approaches will take advantage of the highly localized injuries in FSGS, i.e. the focal and segmental nature of the sclerosing lesions. Colocalization of mediators with expressions of candidate modulators of the disease process, as proposed in this project, is the first essential step in fulfilling Koch's postulates for establishing a causal role in disease, which can then be explored in complementary studies, e.g. cell culture, proteomic, genomic analyses in future studies. A key element will be the correlation of renal biopsy tissue findings with clinical outcome, to determine markers of prognosis and therapeutic response. These translational studies will utilize findings from the clinical specimens to provide an initial test of the putative pathogenetic roles of the leading molecular "suspects" that result in FSGS. These approaches could ultimately identify novel therapeutic targets in FSGS.